Gas-Phase Base-Catalyzed Claisen-SchmidtReactions of the Acetone Enolate Anion withVarious Para-Substituted Benzaldehydes

George W. Haas"Department of Chemistry, University of Nebraska-Lincoln, Lincoln, Nebraska, USA

Michael 1. GrossDepartment of Chemistry, Washington University, St. Louis, Missouri, USA

Substituent effects were determined for the gas-phase base-catalyzed Claisen-Schrnidt reac­tion of the acetone enolate anion and various para-substituted benzaldehydes. Under chemi­cal ionization conditions, the adduct for the reaction was detected and the fraction of adductthat is tetrahedral was determined. The Hammett constants for the substituents correlate thefraction of the adduct population that is tetrahedral. The fraction of tetrahedral intermediateis greatest for those systems in which the negative charge is most highly stabilized. Thestructures of the adducts are determined on the basis of collisionally activated decompositionmass spectra. These spectra show that both the adducts of the ion-molecule reactions anddeprotonated reference compounds, which have a structure that is similar to the tetrahedralintermediate, decompose by elimination of water and by a retro-aldol reaction. The adductsformed from the ion-molecule reactions show a greater propensity to reform the acetoneenolate, whereas the deprotonated reference compounds eliminate H 20 readily. The reactionconstant p from the Hammett correlation is +1.6, which substantiates that the production oftetrahedral intermediates is facilitated by electron-withdrawing substituents. {J Am Soc MassSpectrom 1996, 7, 82-92)

The first base-catalyzed aldol-condensation reac­tion was carried out in 1880 by Schmidt [1], whoreacted furfural and acetaldehyde. Schmidt also

investigated the reaction of furfural and acetone, whichlater became known as the Claisen-Schmidt condensa­tion [2] (a condensation between an aldehyde and aketone), and that reaction is the first example of amixed-aldol or crossed-aldol condensation.

The aldol condensation is important in biology be­cause it is involved in the biosynthesis of many signif­icant natural products, which include the products ofthe life-sustaining dark reactions of photosynthesis. Asearly as 1887, Fischer and Tafel [3] studied the photo­synthesis product fructose, which was generated in thealdol reaction of an enzyme-catalyzed process.

In the synthetic-organic field, the venerable aldolcondensation has been the subject of renewed interestduring the last two decades [4] owing to the discoverythat the stereochemistry can be controlled by the use ofpreformed enolates [5]. The aldol condensation is oneof the most useful stereoselective reactions among the

Address reprint request to Professor Michael L. Gross, Department ofChemistry, Washington University, 1 Brookings Drive, St. Louis, MO63130.• Current address: Helene Curtis, 3100 Golf Road, Rolling Meadows,IL 60008-4009.

© 1996 American Society for Mass Spectrometry1044-0305/96/$15.00ssnr 1044-0305(95)00587-0

carbon-carbon bond-forming processes [6]; it enablesthe synthesis of larger molecules (e.g., antibiotics [7])with two new functional groups from smaller buildingblocks of molecules.

The commonly accepted mechanism [5, 8] for thegeneral base-catalyzed aldol reaction in solution in­volves the addition of an a-carbon of one aldehyde orketone molecule to the carbonyl carbon of another (seeScheme n The entire system reaches equilibrium, andthe reverse reaction, which is known as the retro-aldolreaction, reforms reactants.

A mechanistic explanation for the stereoselectivitywhen preformed enolate derivatives are used for aldolreactions was proposed by Zimmerman and Traxler[5il, who invoked a six-membered transition state.Although this simple mechanism has received supportsince it was proposed in 1957, recent studies indicatethere are many complexities that require that alternateor modified mechanisms be considered [5d].

Although the liquid-phase aldol condensation hasbeen the subject of an enormous amount of study, onlysince the 1970s have nucleophilic substitutions andadditions to carbonyl centers of negative ion-moleculereactions in the gas phase [9, 10] received much atten­tion. The gas phase provides an opportunity to explorethe intrinsic properties of ionic species and to investi-

Revised July 28,1995Accepted July 281995

J Am Soc Mass Spectrom 1996, 7,82-92 BASE-CATALYZED CLAISEN-SCHMlDT REACTIONS 83

II R,J-R"

o-0-C'R'(R"rCH2~-R

II H20

oII

HO-C'R'(R"rCH2-c-R

+OH

Scheme I

gate ionic intermediates that exhibit high reactivityand are not stable in solution [11]. An underlyingproblem, however, is to sort out competing pathwaysinvolved in the ion-molecule reactions, because onlyionic products are detected. One way to elucidate thereaction pathway is with "chemical probes," which areneutral reagents that, when reacted with an nucle­ophile such as the acetone enolate, yield ionic productsthat can be used to distinguish between carbon andoxygen attack [12]. Brickhouse and Squires [13] usedperfluorinated propene and 6,6-dimethylfulvene, Nib­bering and co-workers [14] utilized perfluorinated aro­matics, and Brauman and co-workers [15] employedtrifluoroacetyl chloride to separate competing path­ways in gas-phase reactions of nucleophiles.

Nevertheless, only a few base-catalyzed aldol con­densations have been characterized in the gas phase.Bouchoux and Hoppilliard [16] and Bowie and co­workers [17] reported the gas-phase aldol reaction ofacetone. Gross and co-workers [18, 19] investigatedboth the gas-phase reactions of the acetone and ac­etaldehyde enolates [18] with their respective neutralsand the Reformatsky condensations [19] of the ethyl­acetate enolate that reacted with acetyldehyde or ace­tone.

In this article, we present the results of the gas-phasebase-initiated Claisen-Schmidt reactions [20] of ace­tone with various para-substituted benz aldehydesand we probe the nature of the covalent adductsas a function of the Hammett fIp substituent para­meter. Variation of the substituents of thebenzaldehyde-acetone system and use of the Ham­mett correlation [21] allow us to determine the natureof the adducts and the extent of stabilization thatoccurs in the formation of tetrahedral intermediatesthat eliminate H 20.

Results and Discussion

Formation of the Adduct

The product of expected mass for the base-catalyzedClaisen-Schmidt reaction is found when the symmetri-

cal acetone enolate, formed by abstraction of H+ byCH 30-, reacts in the gas phase with various benzalde­hydes substituted at the para position with -N02,

Br-, Cl-, -SCH3, H-, -CH3, -OCH3, and-N(CH3) 2' The nucleophilic-addition adducts, whichare formed with excess energy and have little chanceto survive until detection without some means of sta­bilization (e.g., collisions or radiative emission), arecollision-stabilized under the conditions of a chemicalionization (Cl) source at - 0.1 torr (13 Pa). The struc­ture and chemical, properties of the collision-stabilizedadducts from the gas-phase ion-molecule reactionswere studied by examination of both their metastable­ion [22] and collisionally activated decomposition [23]mass spectra. The former indicate the low energy frag­mentation pathways whereas the latter are a measureof the high energy processes. The nature of the adductswas established by comparison of their properties withthose of the deprotonated reference compounds, whichwere prepared by proton abstraction from suitableneutral l3-hydroxy ketones.

Metastable-Ion Studies

Under low energy conditions, both the adduct andreference ions decompose by elimination of H' andH 20, as well as by formation of the mrz 57 ion(presumably the acetone enolate), The nitro-containingadduct and reference ions also decompose by the lossof 47 u, which probably corresponds to HN02 • How­ever, the product ions for both the adducts and thedeprotonated reference compounds are of low abun­dance, which makes accurate assignment of relativeabundances difficult. Despite the low abundances, weconclude that the metastable-ion (MI) mass spectra ofthe adduct and deprotonated reference compounds aresimilar except for the relative abundances of H 20-lossand the retro-aldol product ions; H 20 elimination isattenuated and the retro-aldol product is augmentedfor the adducts of the ion-molecule reactions com­pared to the (M - H) - ions of the reference com­pounds.

Collisionally Activated Decomposition Studies

The collision-activated decomposition (CAD) massspectra of the adduct and the appropriate deproto­nated reference compounds (see Figures 1 and 2 forexample CAD spectra) reveal a wealth of structuralinformation and show a considerable increase of theabundances of product ions compared to those seen inthe MI mass spectra. Both the adduct and the corre­sponding reference anions produce the retro-aldolproduct (the acetone enolate), give fragment ions thatare expected for the particular para substituent, loseneutral acetone to form (in low abundance) the anionof the para-substituted benzaldehyde, and eliminateH 20, H: and H 2 (see Table 1). The data for losses of

84 HAAS AND GROSS J Am Soc Mass Spectrom 1996, 7, 82-92

• 100 aCH,1-e~--@-N-(CH,),-90

10 ~CH,-C-eH3

70 --.........60

-H,o

t 50

40

30-H,O

20011020

80

_________.80 x999_.80.

Col 20

~ 10

~:::J O-\-..........................."'T""........J:L,..........":1:""'.........~.........~-.4:T.""a.-r......r:=.=.r-.:l 0 60 80 100 120 140 160

~ ----------.,00----------~ 100 b~ 90

•

200110

1\1\ JI.10 100 120 140 1606040

~~ HJ~O'30CH,-e-CJl, V~ NO, ~

-HNO,

20

----------:.80----------~ 9H -H'

CH,-e-eH,T*NO,--------H

50

40

30

100 a90

10

70

60

-H,O

"

604020

70

10

30

20

50

40

60

A J. A. lI.80 100 120 140 160 110 200

mlz

Figure 2. The CAD spectrum of the adduct (a) of III/Z 206formed by the reaction of acetone enolate anion with p-dimethyl­aminobenzaldehyde and (b) of the deprotonated 4-( p-dimethyl­aminophenyD-4-hydroxy-2-butanone of 111/: 206.

200

-H,o

\-HNO,

t

140 160 110

A

120806020

4.

80

70

60

50

3.

20

1.IDD

mlz

Figure 1. The CAD spectrum of the adduct (a) of III/Z 208formed by the reaction of acetone enolate anion with p-nitro­benzaldehyde and (b) of the deprotonated 4-( p-nitropheny])-4­hydroxy-2-butanone oflll/z 208.

Table 1. CAD mass spectra of the adduct ions from the ion-molecule reactions of acetone/p-benzaldehydes and the(M - H)- ions of the reference l3-hydroxy ketones'

Losses from adduct and (M - H)- ions (relative abundance) Formation ofSubstituent/system b H H2 H2O X'C6H 4-CHO (CH 3 )2 CO X-

- N0 2/IMR 65 3.2 100 47 62 33

-N02/Ref 15 2.6 100 8.2 11 6.2

-Br/IMR 46 21 47 100 16 11

-Br/Ref 17 10 100 15 3.5 4.0

-CI/IMR 8.5 16 37 100 10 1.7

-CI/Ref 7.4 12 100 33 3.5 1.0

-SCH3/IMR 3.0 11 14 100 8.6

-SCH3/Ref 6.2 8.2 100 22 2.8

-H/IMR 7.8 8.4 8.9 100 1.3

-H/Ref 11 9.5 100 36 0.44

-CH3/IMR 5.0 10 6.1 100 36

-CH3/Ref 6.9 9.0 100 35 13

-OCH3/IMR 0.86 3.4 1.5 100 6.9

-OCH3/Ref 2.6 11 100 20 0.86

- N(CH 3 )2/IMR 1.0 0.77 0.30 100 4.4

- N(CH 3 )2/Ref 4.9 3.4 100 50 4.3

• Not all fragmentations associated with the para substituent for both adduct and reference ions are given.b IMR indicates an ion-molecule reaction; C Ref indicates the appropriate reference compound.

) Am Soc Mass Spectrom 1996,7,82-92 BASE-CATALYZED CLAISEN-SCHMIDT REACTIONS 85

HN02 from both the nitro-substituted adduct and thecorresponding deprotonated reference compounds areomitted from the table because the other adducts andthe deprotonated reference compound have para sub­stituents that are not eliminated to appreciable extents.

Formation of the Acetone Enolate Anion

The major fragment ion observed consistently in theCAD spectra of the adducts of the gas-phaseClaisen-Schrnidt reactions is the acetone enolate ofmlz 57. The deprotonated reference compounds showa markedly lower propensity to form this enolate.Confirmation that the anion of mlz 57 is the acetoneenolate was obtained by sequential collisional activa­tion (MS3

) experiments, which are designed to exam­ine an ion that is a product of a decomposition reaction[24]. The precursor is selected and activated to producethe product of interest. Upon consecutive activation,the product is examined by either its metastable-ion orcollisionally activated decompositions. Although theMS3 experiments suffer from poor sensitivity, theypermit both the selection of the putative enolate,formed from either the collision-stabilized adduct orthe deprotonated reference compounds, and the acqui­sition of its CAD spectrum. For example, the CADspectra of the mr z 57 ions from the deprotonated4-phenyl-4-hydroxy-2-butanone and of the adduct fromthe appropriate ion-molecule reaction are nearly iden­tical to that of the authentic acetone enolate, whichwas formed from acetone by deprotonation with-OCH 3·

The loss of neutral benzaldehyde to form the ace­tone enolate from the deprotonated reference com­pounds occurs via a retro-aldol mechanism from struc­ture 1 in eq 1. Aldol-condensation products in theliquid phase, under the right conditions, also undergoa retrograde reaction to reform reactants.

(1)

Structure 1 is produced directly by abstraction ofH+ by CH30-, but abstraction of H+ can occur fromother sites, generating structures 2 and 3, for example.These latter structures form because the conjugate baseof CH30H is stronger than the anions (1,2, and 3). Thegas-phase acidity (LlGacid ) of CH30H is 1565 kllmol[25], whereas the gas-phase acidities that govern theionization of the hydroxyl proton (shown removed in1), the proton located alpha to both the ketone andhydroxyl groups (shown removed in 2), and the protonfrom the methyl group located alpha to the ketonegroup (shown removed in 3) are not available for the

compounds studied here. However, the gas-phaseacidities should be comparable to those of the struc­turally similar compounds benzyl alcohol (1519klimon, acetylacetone (1406 klimon, and acetone(1515 klimon, respectively [25]. Although these com­pounds are not perfect models for 1-3, the differencesin acidity between 2 and 1 or 2 and 3 are significant.The most exothermic reaction is to abstract a protonalpha to the ketone and hydroxyl groups to formstructure 2. Thus, the highest fraction of deprotonatedspecies from the reference compounds is expected tobe 2. Structures 2 and 3, however, cannot produce theacetone enolate directly without first undergoing pro­ton transfer to form 1.

The adducts from the ion-molecule reactions, asmentioned earlier, also decompose to give the acetoneenolate, but with greater facility than do the reference(M - H) - ions. The increased abundance of the eno­late formed from the Claisen-Schmidt reaction adductis attributed partially to preferred production of 1,referred to as the tetrahedral intermediate. This struc­ture can generate the acetone enolate directly, whereasstructures 2 or 3, which are not formed directly butrequire a proton transfer, cannot. There is a populationof structures 1-3 associated with the adducts that isdifferent than that formed by deprotonation of thereference compounds. Structure 1 is preferred for theadducts, whereas ion 2 is favored thermodynamicallyby approximately 84 kllmol, and it fragments princi­pally by expelling water but not undergoing the retro­aldol reaction.

Facile production of the acetone enolate also can beenvisioned to occur through a simple fragmentation ofloosely bound adducts such as the ion-neutral com­plexes 4 and 5 or the proton-bound complexes 6. For areview of these species in which an ion is coordinatedto a neutral molecule or radical by weak forces such asion-dipole attraction, the reader is directed to severalexcellent reviews [26]. Loosely bound adducts wereproposed previously by Gross and co-workers [18, 19]to occur in similar aldol condensations and in Refor­matsky reactions. Structures 4, 5, and 6 are possiblebecause the acetone enolate is released from theadducts, particularly from those with electron­releasing groups. Additional evidence for structures4 and 6 is their property to fragment to a deprotonatedbenzaldehyde.

Another intermediate that can decompose readily tothe acetone enolate would form through an oxygenattack (see eq 2). Even structures associated with 4, 5,and 6, where the negative charge resides predomi­nately on the oxygen, can dissociate to form the ace-

-{5\--JH? - ~x--~~:r.-Cli-C-CH.I

Ii2

86 HAAS AND GROSS

o~-H

r&..........~'c-eHJ¥ H~X 5

Ion-Neutral Complexes

J Am Soc Mass Spectrom 1996,7,82-92

for the reactions of p-nitrobenzaldehyde and p-di­methylaminobenzaldehyde, respectively, with the ace­tone enolate.

~N+~tH_·:y-o-tH (3).0 .

o 0

-@-II - _\\X C 1l........H....•..ll .~C-CH)

H2C

6

Proton-bound Complex

tone enolate. It is difficult to sort out these competingpathways for ion-molecule reactions, and this systemis no exception. On the basis of CAD spectra of theadducts and deprotonated reference compounds, asmall fraction of adducts that originates from oxygenattack of the acetone enolate at the carbonyl carbon ofbenzaldehyde cannot be ruled out. The elimination ofwater from 7 would be difficult to rationalize, and thisis the topic of the next section.

(2)

Elimination of Water

The elimination of water is the most facile reaction ofthe deprotonated reference compounds. The departureof H 20 from ,B-dicarbonyl compounds [27] and fromsimilar gas-phase aldol-condensation and Reformatskyreaction products was shown previously to be charac­teristic of a tetrahedral species. The route for waterloss from the ,B-hydroxy ketones, however, was notelaborated for the deprotonated reference compoundsor for adducts of structures similar to 1-3. We proposehere that the elimination of H 20 occurs predominantlyfrom that fraction of covalently bound adducts thatexist as structure 2. Water loss cannot occur from 1directly without proton transfer to form 2. Structure 3can be envisioned to lose H 20 via a charge-remote1,2-elimination, but this is probably a less facile routethan that for water elimination from 2. Elimination ofH 20 via a loosely bound adduct (4,5, or 6) or throughan oxygen-attack adduct (7) is highly unlikely.

The propensity for water elimination from the ad­duct becomes considerably attenuated as the electron­releasing character of the para substituent increases.Electron-withdrawing groups pull electron densityfrom the carbonyl carbon of the benzaldehyde, whichcreates a greater partial positive charge on the car­bonyl carbon and makes it more susceptible to nucle­ophilic attack. This effect is illustrated in eqs 3 and 4

(4)

Mechanism for Water Loss

The mechanism for the elimination of water was inves­tigated to determine the oxygen and hydrogens thatare involved in the fragmentation. To determine whichoxygen is involved, a CAD spectrum was obtained forthe ion that is formed by loss of water from theadduct. The ion was produced in the ion sourcethrough the reaction of acetone and p-chlorobe­nzaldehyde. The spectrum of the adduct is nearlyidentical to that of the (M - H - H 20 ) - ion of theappropriate reference compound (see Figure 3a for theCAD spectrum of the adduct from the ion-moleculereaction). The major fragments are a low abundancemrz 41 ion (probably the conjugate base of ketene) andthose ions produced by losses of CH 3 and 42 u (mostlikely ketene). These fragment ions are consistent withelimination of the benzaldehyde carbonyl oxygen (i.e.,the oxygen of the carbonyl involved in the nucleophilicaddition) as part of the expelled water. The liquid­phase Claisen-Schmidt reaction product also dehy­drates analogously to give benzalacetone [28].

To verify that the putative (adduct - H 20 ) - formedin the ion source is the same as the ion formed fromthe adduct, an MS3 experiment was conducted. TheCAD spectra, obtained in the MS3 mode, of the (ad­duct - HP)- and of the (M - H - H 20 ) - of thereference compound are nearly identicaL One differ­ence is that CH 3 is eliminated with greater propensitythan when the source-produced (adduct - H 20 ) ­and (M - H - HzO)- are activated (compare Figures3a and b). The spectra for the source-produced ionsandions produced by collisional activation (CA) are dif­ferent, possibly because the ions are formed underdifferent conditions and, as a result, have differentinternal energy. This was tested by collisional activa­tion of the source-produced (M - H - H 20 ) - ion inthe first collision cell, and then selection of those acti­vated but undecomposed ions for subsequent study.This was accomplished by suppression of the mainbeam by 80%, as was done in the MS3 experiments,and closure of the beta slits after the first electrostaticanalyzer to select the low translational-energy ionsfrom the collisions. The spectrum of the energized(M - H - H 20 ) - ion from the adduct of theion-molecule reaction is now similar to those of theion-molecule and reference ions that are produced inthe ion source (see Figure 3c).

J Am Soc Mass Spectrom 1996, 7, 82-92 BASE-CATALYZED CLAISEN-SCHMIDT REACTIONS 87

2"

-HDO

-HDO

ID 100 120••4.

_ ?iCDz-C-<:Dz

<,

_----------.'0000'-----------

~.7e

••

..

40

3'co~ 20..

't> 10

"",Q 0« • 20co>~100

bgll: 90

80

70

.0

~o

'0

a

10

20

30

9•

,.._----------.'00'---------

12•

AAI:!\I••

••/..

..2. vo 1()O 120

"" ---------:.175-------:::-:--," b

<.l~ ID

~ 7.I::I ••.Q< ~.

~ ..~ 3D

;g 2.

"

...Of

JO

a

"

••

.... ---------:.400-------=--

Figure 3. (a) CAD spectrum of the source-produced (adduct ­HzO)- ion (mlz 179) from the acetoneyp-chlorobenzaldehydereaction. (b) CAD spectrumof the (M - H - HzOr ion from4-( p-chlorophenyD-4-hydroxy-2-butanone obtained in the MSJ

mode: 197 -> 179 -> products. (c) CAD spectrum of the source­produced (adduct - HzO)- ion (mlz 179) activated by colli­sions in the first collision cell and activated for decomposition inthe second collision cell.

The source-produced (adduct - H 20 ) - ions fromthe reaction of acetone with p-nitrobenzaldehyde andthe (M - H - H 20 ) - ions of the corresponding refer­ence compounds also were investigated. Their CADspectra are very similar and show that a facile loss ofCH 3 occurs just as it does in the MS3 experiments thatinvolve the (adduct - H 20 ) - of the reference com­pound. The CAD spectra of the source-produced andthe CA-produced ions that come from water loss arenearly identical.

To discern the origin of the two hydrogen atoms onthe departing water, acetone-a, was reacted with p­chlorobenzaldehyde to form an adduct of I11/Z 202.The mass-to-charge ratio of the adduct is additionalevidence that it is the acetone enolate anion that reactsin the ion source with the various p-substituted ben-

••2. 60 10 100 120 140 160 110 200

mlz

Figure 4. (a) CAD spectrum of the adduct of mlz 202 formedin the reaction of acetone-db enolate anion and p-chlorobe­nzaldehyde. (b) CAD spectrum of the deprotonated 4-( p-chloro­phenyD-4-hydroxy-2-butanone-1,1,1,3,3-ds of mlz 202 (insetsshow expanded views of the region of the spectrum that containpeaks of 020' HDO, and H 20 losses).

zaldehydes. The CAD mass spectrum of the I11/Z 202adduct (see Figure 4a) shows that H 20 , HOO, andD20 are eliminated in a ratio of 1.2:5.0:1.75/ respec­tively (average of four determinations). The deproto­nated reference compound, 4-{ p-chlorophenyD-4­hydroxy-2-butanone-l/1,1/3/3-dS' eliminates H 20 ,HDO, and D20 upon CA in a ratio of 1.3:5.0:1.5/respectively (see Figure 4b). For complete equilibrationof hydrogen atoms, the ratio is 2.0:5.0:2.0. When wetest other hypotheses that complete equilibration in­volves an equal number of exchangeable hydrogensand deuteriums that total eight, six, or four, we predictlosses of H 20 , HOO, and D20 in ratios of 1.87:5.00:1.87/1.67:5.00:1.67/ and 1.25:5.00:1.25/ respectively. Othercombinations that involve different numbers of hydro­gens and deuteriums do not produce a match for theloss pattern.

One explanation for the observed water-loss pattern(see Scheme II) holds that elimination of water fromthe adduct begins with a proton transfer, which pro­duces a hydroxyl group, followed by the formation ofa carbon-carbon double bond and ejection of a hy­droxyl ion to give an ion-neutral complex, 8. Whenthe reference compound is deprotonated by - OCH3, 2can be formed directly. The OH- is held by an ion­dipole interaction and can abstract a proton from vari­ous positions. Abstraction from the vinylic positionsforms complexes 9 or 12, whereas abstraction of an

"'All,

'2'1 1,

.. mlz'"2.

c

"

••

••

9'

3.

••

2'

7.

88 HAAS AND GROSS ] Am Soc Mass Spectrom 1996,7,82-92

Scheme II

HzO)- ions from the reference compounds give CADspectra that indicate methyl loss and ketene elimina­tion are significant (see Figure 3a). When the (adduct­HzO)- ion is formed through a CAD process or iscollision-activated prior to acquisition of its CAD spec­trum (see Figure 3b and 3c, respectively), the loss ofmethyl dominate, which suggests that water elimina­tion from structure 10 is not important.

Following proton transfer, water loss also can occurfrom 1 through a six-membered ring as shown inScheme III, to form 3. However, this is an alternateroute to 10 [the prime (') is used in Scheme III todenote an isomeric resonance structure); this routeprovides a means for water elimination and scram­bling as shown in Scheme II.

Elimination of H' and Hz

The loss of H' (not D') occurs in both the metastableand collisionally activated decompositions of theadduct, formed by the reaction of acetone-d. enolatewith various p-substituted benzaldehydes, and thedeprotonated 4-( p-chlorophenyD-4-hydroxy-2­butanone-1,1,1,3,3-ds' The fragment presumably hasstructure 13 in eq 5:

Scheme III

The loss of Hz (HD for the labeled adducts and depro­tonated reference compounds) also can occur throughthe tetrahedral intermediate to give 14 shown in eq 6:

-)0(11 IlQi D0 *11fI 0 D0 (6)

x 0 N-g-co; =='" x 0 ~~-~-CD; + HD

H H fJ14

(5)H H _ H H l"'"~D O *0 0X 0 I-{-~-CD; = X 0 ~-cDl-~-CH;

Ii DH H H +H"

13

Indeed, the loss of Hz is indicative of fragmentationof an alkoxide as previously was reported for simplealkoxide anions [31]. The source-produced (adduct ­H z)- ions as well as the (M - H - H z)- ions of thereference compounds, upon subsequent collisional ac-

aryl proton generates 11, and abstraction of a methyl­group proton produces 10. The abstraction of a methylproton is exothermic, and the resulting water can eas­ily depart.

The removal of an aryl proton for the adducts andreference compounds studied here would normally beconsidered an endothermic process, but the ion-dipoleinteraction may return approximately 84 kllmol as thetwo reactants begin to complex [29, 9d]. This interac­tion is particularly favored when the aromatic ringcontains an electron-withdrawing group and explains,in part, the facile water loss from adducts formed froma benzaldehyde that bears an electron-withdrawingsubstituent. Some or all of the excess internal energycontained in the complex may be used to carry out thetransfer, which forms 11. Subsequent proton transfer,which is exothermic, results in exchange of hydrogensprior to dissociation. DePuy and co-workers [30]showed that OH - exchanges with the protons of ben­zene-u, and that 2-phenylallyl anion exchanges eightof its nine protons (at least four of the five aromaticprotons). There is a requirement that the acidity of theC-H bond must be less than the ion-dipole energy ofthe ion-neutral complex.

The two processes, losses of CH 3 and 42 u (ketene)from the (adduct - HzO)- and the reference (M - H- HzO)- ions, are indicative of at least two structuresfor these ions. Methyl loss can be envisioned to occurafter water elimination from 9 and 12 (Scheme II),whereas ketene loss is expected to be a signature of theion formed after water loss from 10. Recall that boththe source-produced (adduct - HzO)- and (M - H -

) Am Soc Mass Spectrom 1996, 7, 82-92 BASE-CATALYZED CLAISEN-SCHMIDT REACTIONS 89

Correlation with Hammett Constants

The Hammett relationship is used here to elucidate theelectronic effects of the substituents on the extent offormation of tetrahedral intermediates (i.e., thoseadducts that eliminate HzO) in the gas-phaseClaisen-Schmidt reaction. The Hammett equation (seeeq 7) is one of the mainstays of quantitativestructure-reactivity relationships in physical organicchemistry:

tivation, eliminate predominantly CHzCO (42 u) andundergo losses of CH 3, CH 4 , and HzO, which arecharacteristic losses of ,B-dicarbonyl [27] aldol­condensation [18] and Reforrnatsky-condensationproducts [19].

The losses of H' and Hz from adducts that containelectron-withdrawing groups are nearly the same asthose from the (M - H) - ions of the reference com­pounds. This indicates that most of the adducts fromreactions in which the benzaldehyde is electron-poorare bound covalently. For reactions of benzaldehydeswith strongly electron-releasing substituents [e.g.,-OCH3 and -N(CH3)z], the losses of H' and Hzfrom the adducts are diminished with respect to thosefrom the references. Calculation reveals that approxi­mately one third of these adducts for the reactions ofthe electron-rich benzaldehydes are bound loosely.

0.5-0.5-I

Para substituent %H 20 loss" Sigma value

NOz 68 ± 5 0.778Br 32 ± 5 0.232CI 27 ± 3 0.227SCHa 12 ± 1 0H 8.2 ± 2.0 0CHa 5.7 ± 2.7 -0.17OCH a 1.5 ± 0.1 -0.268N(CH)a 0.30 ± 0.1 -0.83

orJp

Figure 5. Hammett plot of the relative percent of tetrahedralintermediates (i.e., species that eliminate H 20) with respect to allother adducts for the reactions of the acetone enolate anion withthe various p-substituted benzaldehydes at approximately 0.1torr (13 Pal versus up'

Table 2. Percent of tetrahedral adduct population thateliminates H 20 with respect to adducts that produceacetone enolate

diate is calculated from data in the adductis CADspectra by taking the abundance of the ions producedby water loss and dividing by the sum of the abun­dances of the acetone enolate and the anion producedby water loss.

The percent of tetrahedral adducts with respect toall other adducts of the Claisen-Schmidt reactions (seeTable 2) correlates reasonably well with the Hammettsigma constants (see Figure 5; correlation coefficient is0.921 and the p value is +1.6). This reaction constant,which is a quantitative measure of the relative ten­dency to form a tetrahedral intermediate, is evidencethat this gas-phase Claisen-Schmidt reaction is facili­tated by electron-withdrawing substituents.

The deprotonated reference compounds do not showa correlatable trend for water elimination (see Table 1).Because the deprotonated reference compounds existprincipally as 2, the water elimination is shielded fromthe electronic effects of the para substituents.

Possibility of ipso Substitution

Another route for attack of a nucleophile is on thebenzene ring to give ipso substitution. Ipso substitu-

I.h-----------------~...,

a Standard deviation was for two to five separate determinations.

..---,

" =i~" ":g:g o.-c -eE E~~

W MW Wo 0

...l ...l00-0.

££~e ·1'---'

j -1.

(7)10g( :0) = 10g( :0) = up.

In eq 7, k and K are the rate and equilibrium con­stants, respectively, for the reaction of a substitutedbenzene derivative, and ko and Ko are the rate andequilibrium constants for the unsubstituted com­pound.

Although the Hammett correlation has been used tomeasure substituent effects for gas-phase reactions,Attina and Cacace [32] interjected a cautionary note onthe validity of the approach. They argue that becausethe substituent constants are obtained from equilib­rium and kinetic data for reactions in the liquid phaseat well defined temperatures, they do not apply toion-molecule and fragmentation reactions, which of­ten are conducted at low pressures where the system isnot characterized by a temperature. Nevertheless, theHammett relation has been demonstrated to be usefulto correlate gas-phase reactions that occur in massspectrometers [33].

The Hammett up parameter is used here to probethe extent of negative-charge stabilization provided bythe para substituents of the benzaldehydes in theirreaction with the acetone enolate. We expect the extentof stabilization to determine the fraction of tetrahedralintermediates in a mixed population of structures forthe adduct "isolated" under the conditions of theseexperiments. The fraction that is a tetrahedral interme-

90 HAAS AND GROSS J Am Soc Mass Spectrom 1996,7,82-92

tion should be most favored for a benzaldehyde thathas the strongest electron-withdrawing substituent.Thus, we examined closely the nature of the adductproduced in the reaction of the acetone enolate withp-nitrobenzaldehyde. This system has the highest frac­tion of adduct that exists as a tetrahedral intermediateand permits the closest comparison of the CAD spectraof the adduct and the (M - H)- of the reference com­pound. Upon collisional activation, both species givethe same product ions in similar abundances (see Fig­ure 1a and b), which indicates that there is structuralsimilarity between the adduct and the (M - H)- ofthe reference and rules out any significant ipso substi­tution.

When acetone-a, is reacted with p-nitrobenzalde­hyde, the adduct loses 48 u, which corresponds toDN02 (not HN02 ) . An ion-neutral complex wouldexplain the abstraction of D by NO;. The deuteriumprobably originates from one of the two deuteriumslocated alpha to the ketone on the benzene-ring side ofthe alkyl chain because these are the most acidic.Furthermore, we obtained the CAD spectra of the(adduct - HN02 ) - and of (M - H - HN02 ) - of thereference, by both tandem mass spectrometry and MS3,

and found the spectra to be nearly identical. This alsoindicates that ipso substitution does not occur to anyappreciable extent, but does not explain why variousproduct ions observed in the CAD mass spectra of theion-molecule-reaction ad ducts are of higher abun­dance than those of the appropriate reference (M ­H)- ions (compare, for example, products from theloss of neutral acetone from the adduct and from theappropriate deprotonated reference compound; seeTable 1). The difference may be due to a variation ofthe initially formed structures of the reference andadduct ions, as was discussed already.

Conclusions

The Claisen-Schrnidt reaction of substituted benzalde­hydes and the acetone enolate occurs in the gas phaseto produce an isolatable tetrahedral intermediate alongwith other covalently bound and loosely bound com­plexes. The fraction of the tetrahedral adduct (i.e., thespecies that eliminates H 20) is predictable on the basisof the Hammett relation. As the electron-withdrawingcharacter of the para substituent of the benzaldehydeincreases, the fraction of tetrahedral adducts also in­creases. This conclusion is consistent with the nature ofthe tetrahedral intermediate, structure 2, which is ex­pected to undergo a more facile elimination of waterthan do other covalent adducts and loosely boundion-dipole or hydrogen-bound complexes.

Experimental

The high-pressure experiments were carried out with aKratos Scientific Instruments (Manchester, UK) MS50

triple analyzer mass spectrometer [34] of E1BE2 design(E denotes electrostatic sector analyzer; B denotes mag­net sector analyzer) equipped with a Kratos Mark-Vchemical ionization source. The instrument was oper­ated in the negative-ion mode at an accelerating volt­age of -8 kV, to give an ion-residence time in thesource of :::: 10 us [35]. Precursor-ion selection wasperformed at a resolving power of :::: 5000 unlessinterfering isobars were present; then the resolvingpower was increased to separate the ions. The methylnitrite was leaked into the source through a Kratosreagent-gas inlet system to an indicated source­housing pressure of ::= 7 X 10- 6 torr (9 X 10-4 Pa).Sufficient acetone was delivered to the source via acustom-fabricated reservoir probe equipped with avariable leak valve to give a source-housing pressureof :::: 2 X 10-5 torr (3 X 10- 3 Pa), The liquid para-sub­stituted benzaldehydes were introduced by a custom­fabricated heated glass inlet system via a molecularleak, whereas the solid benzaldehydes were vaporizeddirectly into the source by heating a direct-insertionprobe so that a pressure of :::: 2 X 10-5 torr (3 X 10-3

Pa) was achieved. An indicated source-housing pres­sure of 3-5 X 10- 5 torr (4-7 X 10-3 Pa) correspondedto a pressure inside the source chamber of approxi­mately 0.1 torr (13 Pa).

The metastable-ion and collision-activated decom­position experiments were carried out by selecting theprecursor ion with MS-l, which is comprised of E]B,and scanning the voltage applied to E2 of MS-2 toobtain a spectrum of the product ions. The CAD spec­tra were obtained after collision of the selected ionbeam with sufficient helium introduced to the collisioncell located in the third field-free region to cause a 50%reduction of the selected ion beam. The metastable-ionexperiments were carried out by using the same proce­dure described for the CAD experiments except he­lium was not added to the collision cell. Each spectrumwas the average of 10-50 scans taken at a rate of 30 sper scan.

The MS3 experiments [24] also were conducted onthe Kratos MS50 triple analyzer. The adduct ions fromthe reaction of the acetone enolate anion with thesubstituted benzaldehydes were activated in the firstcollision cell, located in the first field-free region, bycollisions with sufficient helium to cause an 80% re­duction of the ion-beam intensity. MS-1 was used todeliver the product ion of interest to the second colli­sion cell in the third field-free region, where the beamintensity was suppressed by 50% with collisions withhelium. The fragments from the selected product ionwere analyzed by scanning MS-2. MS3 experimentswith reference compounds were conducted by select­ing (M - H)- ions in the first step.

Materials

The para-substituted compounds-4-nitrobenzalde­hyde, 4-bromobenzaldehyde, 4-chlorobenzaldehyde,

J Am Soc Mass Spectrom 1996, 7, 82-92 BASE-CATALYZED CLAISEN-SCHMIDT REACTIONS 91

4-methylthiobenzaldehyde, benzaldehyde, P:tolualdehyde, p-anisaldehyde, 4-dimethylaminoben­zaldehyde, acetone, and sodium hydroxide-were allobtained from the Aldrich Chemical Co. (Milwaukee,WI) and were used without further purification. Thereference compounds were prepared by using a stan­dard procedure [36]. The identities of the referencecompounds were confirmed by their full-scan high­resolution (R = 10,000) electron ionization mass spec­tra, acquired with a Kratos MS50 double focusing massspectrometer. Perfluorokerosene was introduced via aheated inlet to bring the source-housing pressure to::::: 5 X 10- 5 torr. Calibration from mrz 28 to 700 wasachieved at a scan rate of 10 s per decade of mass in atypical run. The reference compounds also were char­acterized by l H NMR spectrometery (General Electric,300 MHz), and the spectra were consistent with theproposed structures.

The methyl nitrite was synthesized according tothe procedure of Hartung and Crossley [37] and Huntet a1. [38].

AcknowledgmentsThis work was supported by the Midwest Center for MassSpectrometry, a former National Science Foundation RegionalInstrumentation Facility at the University of Nebraska (GrantCHE-90172250), and by the NIH Research Resource in MassSpectrometry at Washington University (Grant 2P41RR0954).

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